The objective of this research is to elucidate biochemical aspects of the pathogenesis of brain defects due to metabolic aberrations during gestation or early postnatal differentiation. Our recent discovery of a non-toxic suppressor of phenylalanine hydroxylase, alpha-methylphenylalanine, enabled us to create a new animal model for phenylketonuria. This agent, which induces behavioral deficits in infant rats, will also be given to pregnant ones so as to compare the effects of hyperphenylalaninemia or prenatal versus postnatal brain development. Rats with excessive levels of histidine, tyrosine or leucine during neonatal life or gestation will imitate additional, acquired as well as inborn, aminoacidopathies in man. The planned identification of cerebral biochemical defects, of their age of onset and distinction of reversible alterations from those that are permanent will facilitate the prevention of treatment of maldevelopment associated with these conditions in man. In focussing attention on enzymes in glycine metabolism and on the formation of tetrahydrobiopterine (the essential cofactor in serotonin and catecholamine synthesis) we also hope to detect chemical abnormalities in the brain which may be the common consequence of several aminoacidopathies and thus the common basis for the ensuing deficit in cerebral functions.